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The pharmacokinetics (PK) of several drugs including antimicrobials might be highly altered during extracorporeal membrane oxygenation (ECMO) therapy. We present the change of voriconazole (VRC) PK during ECMO in a critically ill patient who received intravenous VRC at a maintenance dose of 200 mg every 12 h for empirical antifungal therapy. Two PK profiles were drawn before and after the initiation of ECMO therapy. Though the trough levels (both

According to the 2019 World Health Organization (WHO) classification, well-differentiated grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are a new category of cancer of the digestive system. G3 GEP-NET research and treatment are not as robust as those of lower grade (G1/2) NETs and poorly differentiated neuroendocrine carcinomas (NECs). Previously, the management of high-grade NETs was mainly based on NEC therapies, as high-grade NETs were classified as NECs under the previous WHO classification. Despite this, G3 GEP-NETs are significantly less responsive to platinum-based chemotherapy regimens than NECs, due to their distinct molecular pathogenesis and course of pathological grade transition. Patients with advanced G3 GEP-NETs, who have progressed or are intolerant to chemotherapy regimens such as capecitabine plus temozolomide, have limited treatment choices. Immunotherapy has helped patients with a variety of cancers attain long-term survival through the use of immune checkpoint inhibitors. Immunotherapies, either alone or in combination with other therapies, do not have a clear function in the treatment of G3 GEP-NETs. Currently, the majority of immunotherapy studies, both prospective and retrospective, do not reliably differentiate G3 GEP-NETs from NECs. By contrast, a significant number of studies include non-GEP neuroendocrine neoplasms (NENs). Therefore, there is an urgent need to summarize and evaluate these data to provide more effective therapeutic approaches for patients with this rare tumor. The purpose of this mini-review was to screen and summarize information on G3 GEP-NETs from all studies on NENs immunotherapy.

We report a facile but general method to prepare highly water-soluble and biocompatible photoinitiators for digital light processing (DLP)-based 3D printing of high-resolution hydrogel structures. Through a simple and straightforward one-pot procedure, we can synthesize a metal-phenyl(2,4,6-trimethylbenzoyl)phosphinates (M-TMPP)-based photoinitiator with excellent water solubility (up to ∼50 g/L), which is much higher than that of previously reported water-soluble photoinitiators. The M-TMPP aqueous solutions show excellent biocompatibility, which meets the prerequisite for biomedical applications. Moreover, we used M-TMPP to prepare visible light (405 nm)-curable hydrogel precursor solutions for 3D printing hydrogel structures with a high water content (80 wt %), high resolution (∼7 μm), high deformability (more than 80% compression), and complex geometry. The printed hydrogel structures demonstrate great potential in flexible electronic sensors due to the fast mechanical response and high stability under cyclic loadings.

(2-dimethyl amino)ethyl methacrylate (DMA) was co-polymerized with (2-dibutyl amino)ethyl methacrylate (DBA) to form random copolymer P(DMA-co-DBA) with DMA/DBA molar ratios in the range of 9:1 to ...

A low-loss all-straight optical fiber vector magnetic field sensor (OFVMS) based on magnetic fluid (MF) is designed and proposed. The sensing structure is composed of a Section of the C-type optical fiber (CTF) embedded in a pair of multi-mode optical fibers (MMF) and wrapped in a capillary with MF. The asymmetry of the CTF provides support for the vector magnetic field measurement whose direction is perpendicular to the optical transmission direction. According to the results of experiments, it can be obtained that the refractive index (RI) sensitivity of the sensing structure is as high as −15716.6072 nm/RIU. In addition, the intensity sensitivity of the OFVMS in the calibrated 90° direction can reach 202.23 pm/G between 0 and 123 G. At the same time, the transmission loss of the proposed sensor structure is not increased by the filling of MF. The sensor demonstrated has dominance in low cost, easy manufacture, and lower loss compared with the same type of sensor device, which has application prospects in vector magnetic field sensing.

STUDY OBJECTIVES This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN Prospective pharmacokinetics study. SETTING The intensive care unit in a tertiary-care medical center. PATIENTS A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Lacustrine shale is an important target for the exploration of unconventional oil and gas in China beyond marine shale gas. However, the formation environment of lacustrine shale differs from that of marine shale, resulting in a different reservoir composition, organic matter, oil and gas content, and hydrocarbon mobility. In this study, the Chang 7 shale of the Yanchang Formation in the Ordos Basin was used to analyze the effect of volcanic activity on the paleoproductivity and preservation conditions during the formation of lacustrine shale. The results show that algae and bacteria were developed before the eruption. After the eruption, the number of bacteria declined, but the increased prosperity of algae reflects that the volcanic activity enhanced ancient productivity. The sulfate generated by volcanic activity promotes bacterial sulfate reduction, and the produced H2S leads to a strong reducing environment in the waterbody, which is conducive to the preservation of organic matter. Organic geochemical analysis shows that the black shale in the shale strata has a high total organic carbon (TOC) content and strong hydrocarbon generation potential, whereas the tuff has a low TOC content and can scarcely generate hydrocarbons, indicating that the tuff deposited by volcanic activity cannot be considered as effective source rock. In terms of storage space, shale is mainly laminar and dispersed, and it includes organic and inorganic pores. The development of organic pores is affected by thermal maturity, whereas inorganic pores mainly occur between detrital particles and crystals. Tuff is mainly supported by heterogeneous matrix and associated with alteration. Its pores include inter- and intragranular mineral pores. The development of tight sandstone pores is affected by compaction, cementation, and dissolution, which mainly consist of intra- and intergranular pores. The Chang 7 lacustrine shale generally contains oil, but different lithologies have different oil drainage efficiencies. Sandstone and shale exhibit the best and worst oil drainage efficiency, respectively. It is mainly affected by the pore size distribution, fluid properties, and rock wettability. Therefore, the development of shale oil should mainly focus on lacustrine shale formations with interbeds. The mutual dissolution of organic matter and hydrocarbons in the shale section leads to the poor mobility and difficult development of hydrocarbons.

Post-translational modification (PTM) on protein plays important roles in the regulation of cellular function and disease pathogenesis. The systematic analysis of PTM dynamics presents great opportunities to enlarge the target space by PTM allosteric regulation. Here, we presented a framework by integrating the sequence, structural topology, and particular dynamics features to characterize the functional context and druggabilities of PTMs in the well-known kinase family. The machine learning models with these biophysical features could successfully predict PTMs. On the other hand, PTMs were identified to be significantly enriched in the reported allosteric pockets and the allosteric potential of PTM pockets were thus proposed through these biophysical features. In the end, the covalent inhibitor DC-Srci-6668 targeting the PTM pocket in c-Src kinase was identified, which inhibited the phosphorylation and locked c-Src in the inactive state. Our findings represent a crucial step toward PTM-inspired drug design in the kinase family.

(1) Background: CD163, a specific macrophage receptor, affects the progression of malignant tumors. Unfortunately, the regulation and expression of CD163 are poorly understood. In this study, we determined the expressions of CD163 in TMA samples from CRC patients and combined them with patient data from several Swedish hospitals. (2) Methods: The expressions of CD163 in tissue samples from CRC patients were examined. After combining 472 CRC patients’ gene expression and 438 CRC patients’ clinical data with the TCGA database, 964 cases from the GEO database, and experimental expression data from 1247 Swedish CRC patients, we selected four genes (PCNA, LOX, BCL2, and CD163) and analyzed the tumor-infiltrating immune cells (TICs) and CRC prognosis. (3) Results: Based on histopathological TMA analysis, CD163 was strongly expressed in the stroma of both normal and cancer tissues, and the expressions in normal and cancer cells varied from negative to strong. The results from public databases show decreased expression of CD163 in cancer tissue compared to normal mucosa (|log FC| > 1 and FDR < 0.01), and it is a negative prognostic factor for CRC patients (p-value < 0.05). Through tumor microenvironment (TME) analysis, we found a potential influence of CD163 on immune cell infiltration. Furthermore, the enrichment analysis indicated the possible interaction with other proteins and biological pathways. (4) Conclusions: CD163 is expressed differently in CRC tissue and is a negative prognostic factor. Its expression is associated with the TME and tumor purity of CRC. Considering all results, CD163 has the potential to be a predictive biomarker in the investigation of CRC.

(1) Background: CD163, a specific macrophage receptor, affects the progression of malignant tumors. Unfortunately, the regulation and expression of CD163 are poorly understood. In this study, we determined the expressions of CD163 in TMA samples from CRC patients and combined them with patient data from several Swedish hospitals. (2) Methods: The expressions of CD163 in tissue samples from CRC patients were examined. After combining 472 CRC patients' gene expression and 438 CRC patients' clinical data with the TCGA database, 964 cases from the GEO database, and experimental expression data from 1247 Swedish CRC patients, we selected four genes (PCNA, LOX, BCL2, and CD163) and analyzed the tumor-infiltrating immune cells (TICs) and CRC prognosis. (3) Results: Based on histopathological TMA analysis, CD163 was strongly expressed in the stroma of both normal and cancer tissues, and the expressions in normal and cancer cells varied from negative to strong. The results from public databases show decreased expression of CD163 in cancer tissue compared to normal mucosa (|log FC|gt; 1 and FDRlt; 0.01), and it is a negative prognostic factor for CRC patients (

Exposure to cadmium (Cd) is associated with cardiovascular diseases. Maternal Cd exposure is a significant risk factor for congenital heart disease. However, mechanisms of Cd on developmental cardiotoxicity are not well defined.We evaluated the effects of Cd on the different stages (mesoderm, cardiac induction, cardiac function) of cardiac development using an early embryo developmentEmbryonic stem cells (ESCs) form 3D aggregates, called embryoid bodies, that recapitulate events involved with early embryogenesis (e.g., germ layer formation). This model was used for early germ layer formation and signaling pathway identification. The 2D cardiomyocyte differentiation from theCd (In conclusion, using a human ESC-derived 2D/3D

Purpose: We aimed to investigate the effect and significance of the rotation method corrected for the depth of two kidneys on the determination of glomerular filtration rate (GFR) in total and single kidneys by the renal dynamic imaging Gates method. Methods: Seventy-two patients who underwent dynamic renal imaging by the rotation method and abdominal CT in our hospital were collected in the present study. CT scanning, rotation method, Tonnesen's formula, and Li-Qian's formula were compared in terms of the depth of two kidneys, depth difference between the two kidneys, and the total renal and single GFR obtained by substituting the renal depth values into Gates' formula. Results: ①GFR and the depth of kidneys: Compared to CT, Tonnesen's formula significantly underestimated the total and single renal GFR and the depth of both kidneys (P < 0.05). No significant differences were found in the total and single renal GFR and the depth of both kidneys between Li-Qian's formula and the rotation method (P > 0.05), with a strong agreement and with the least bias in the values measured by the rotation method. ②Renal depth difference: Compared to CT, Tonnesen's formula and Li-Qian's formula underestimated the difference in depth between the two kidneys (P < 0.05). None of the differences were statistically significant based on the rotation method (P > 0.05). The depth difference was positively correlated with the resulting changes in single renal function (|R(CT)-R(Li-Qian)|) and (|R(rotation)-R(Li-Qian)|) (r = 0.881, 0.641, P < 0.001). As the depth difference increased, Li Qian's formula could not visualize changes in single renal function accurately. In contrast, the accuracy of the rotation method in assessing single renal function remains unaffected. Conclusion: The rotation method obtains an accurate depth and depth difference between the two kidneys without additional CT radiation, enhancing the accuracy of the Gates method for determining total and single renal GFR. Trial registration: Medical Ethics Committee of First Hospital of Shanxi Medical University, 2021BAL0146. Registered 12 January 2021.

Glaucoma is an optic neuropathy, and the leading cause of irreversible blindness worldwide. However, the early detection of glaucoma remains challenging as chronic forms of glaucoma remain largely asymptomatic until considerable irreversible visual field deficits have ensued. Thus, biomarkers that facilitate early diagnosis and treatment for patients with a high risk of progression are critical. Network medicine approaches can be useful in identifying key relationships and important biomolecules for complex diseases. In this paper, we identified several hub biomarkers/drug targets for the diagnosis, treatment and prognosis for glaucoma and explored their associations for glaucoma based on human disease-biomarker and disease-target-drug networks. These results were verified by text-mining and genomic/epidemiology data. We also predicted the new application of BMP1 and MMP9 to diagnose glaucoma and confirm the theory of hub biomarkers with multiple clinical applications. Further, relevant pivotal pathways (regulation of the multicellular organismal process, regulation of localisation, and cytoplasmic vesicle for biomarkers; signal transduction and developmental process for targets) for these hub biomolecules were discovered, which may be foundations for future biomarker and drug target prediction for glaucoma. In conclusion, based on complex networks, hub biomolecules, essential pathways, and close diseases were identified for glaucoma in diagnosis, treatment and prognosis.

Polycythemia vera (PV) is a malignant clonal hematological disease of hematopoietic stem cells characterized by the proliferation of peripheral blood cells, and JAK2 mutation is one of the main causes of PV peripheral blood cell proliferation. Abnormal cell metabolism is a new feature of malignant proliferation of tumor cells, but the role of metabolism in the pathogenesis and prognosis of PV remains unclear. We analyzed metabolic differences of peripheral blood sera between 32 PV patients and 20 healthy controls (HCs) by liquid chromatography–mass spectrometry (LC–MS) to investigate their relationship with cell proliferation and to screen for prognosis-related metabolic biomarkers. Compared to HC, 33 endogenous metabolites were significantly changed in PV and were involved in fatty acid metabolism, glucose metabolism, sphingolipid metabolism, and amino acid metabolism pathways. Among them, seven metabolites were closely associated with JAK2 mutations, 2 of which may contribute to the proliferation of peripheral blood cells in PV patients. A set of potential prognostic metabolic biomarkers containing four metabolites was identified by a receiver operating characteristic (ROC) curve according to the risk stratification of the PV patients and their combined AUC value of 0.952, with a sensitivity of 90.905% and specificity of 90.909% at the optimal cutoff point. Metabonomics is an important tool for the study of the pathogenesis of PV and the relationship between JAK2 gene mutation. Furthermore, the potential biomarkers of this study may provide a reference for the prognosis of PV.

Background Three-dimensional computed tomography bronchography and angiography (3D-CTBA) provides detailed imaging information for pulmonary segmentectomy. This study was performed to verify the feasibility of 3D-CTBA-guided thoracoscopic segmentectomy for the treatment of pulmonary nodules. Methods A retrospective analysis was performed on all patients who underwent 3D-CTBA-guided uniport thoracoscopic segmentectomies or subsegmentectomies for pulmonary nodules in the period from May 2019 to May 2020. All of the information related to perioperative management and surgical operations was retrieved from the medical records and operating notes for detailed analysis. Results A total of 104 eligible operations involving the resection of 110 nodules with diameters in the range of 5-20 mm were included. Under 3D-CTBA guidance, the pulmonary nodules were located with an accuracy of 100% (110/110) and the median resection margin was 24.3 mm (17-33 mm). Additionally, the segmental (subsegmental) bronchi, arteries, and veins were identified with accuracy rates of 100% (104/104), 96.2% (100/104), and 94.2% (98/104), respectively. The postoperative complications consisted of 3 cases of pulmonary infection (2.9%), 6 cases of arrhythmia (5.8%), 2 cases of hemoptysis (1.9%), 4 cases of air leak (3.8%), and 2 cases of subcutaneous emphysema (1.9%). No perioperative death occurred. Conclusion 3D-CTBA-guided thoracoscopic segmentectomy is an effective surgical approach for the management of pulmonary nodules.

A simple method to measure the length of optical fiber is proposed using microwave photonic technology. The length of fiber is measured according to the free spectral range (FSR) of the microwave photonic system. The measurement accuracy is only related to the accuracy of FSR measurement. The accuracy is further improved by introducing a reference fiber, and the method was verified in the experiment with 2–10 m single-mode fiber.

Waste bamboo-derived activated carbon (BAC), biomass char (BBC), and nitric acid-modified BACN and BBCN supports as well as commercial activated carbon (AC) and corresponding ACN were prepared for comparative study. Their denitrification performance in 100–250 °C decreased as BACN > ACN > BBCN > BAC > AC > BBC. BACN and ACN were separately loaded with different MOx (M = Mn, Ce, Fe, Cu, V) by wet impregnation. M/BACN showed slightly higher NO conversion than corresponding M/ACN. Mn/BACN exhibited the best denitrification performance with NO conversion of 92% at 200 °C. The physicochemical properties of supports and catalysts were characterized by BET, SEM-EDS, FTIR, XRD, and XPS. The results suggested that BAC was most sensitive to HNO3 modification, thereby BACN possessed much more surface functional groups. This was the main reason for BACN exhibiting the best denitrification performance among the supports. Loading metal oxides introduced more strong active sites sharply increasing the catalytic activity, even though decreased the surface area and decomposed a few surface functional groups. Mn/BACN mainly followed the L–H mechanism at low temperature. Rich surface functional groups on BACN could promote the adsorption and activation of NH3 and NO accelerating the reaction in L–H mechanism.

Background Research shows that nano-bioceramics can modulate the differentiation of dental stem cells. The novel ready-to-use calcium-silicate-based root-canal sealer iRoot SP is widely used in root filling. Accordingly, the aim of this study was to evaluate the effects of iRoot SP on proliferation and osteogenic differentiation in human stem cells from the apical papilla (hSCAPs). Methods hSCAPs were isolated and characterized in vitro, then cultured with various concentrations of iRoot SP extract. Cell proliferation was assessed by CCK-8 assay, and scratch-wound-healing assays were performed to evaluate cell-migration capacity. hSCAPs were then cultured in osteogenic medium supplemented with iRoot SP extracts. Alkaline phosphatase (ALP) activity assay was used to evaluate ALP enzyme levels. Alizarin red staining and cetylpyridinium chloride (CPC) assays were performed to assess calcified-nodule formation and matrix-calcium accumulation of hSCAPs. The mRNA and protein expression levels of the osteogenic markers OCN, OSX, Runx2, and DSPP were determined by qRT-PCR and Western blotting. The data were analyzed using one-way ANOVA and LSD-t tests. Results iRoot SP at low concentrations (2, 0.2, and 0.02 mg/mL) is nontoxic to hSCAPs. iRoot SP at concentrations of 0.02 and 0.2 mg/mL significantly increases cell-migration capacity. In terms of osteogenic differentiation, 0.2 mg/mL iRoot SP promotes intracellular ALP activity and the formation of mineralized nodules. Moreover, the expression of osteogenic markers at the mRNA and protein levels are upregulated by iRoot SP. Conclusion iRoot SP is an effective filling material for periapical bone regeneration.

An accurate prediction of the hydrogen behaviors in the accident and management process is a crucial topic for both the hydrogen safety assessment and safety analysis in the confined enclosure like the containment of the nuclear power plant (NPP). Hence, the hydrogen behaviors including the transient light gas release, stratification and dissolution in the TH22 test facility for the NPP containment are analyzed and compared using the 3-D CFD code GASFLOW-MPI in this study. In this paper, the light gas helium is adopted as a substitute for the hydrogen in the calculations in accordance with the experiment. Firstly, the detached eddy simulation (DES) turbulence model, 3-D numerical model and experiment setup are introduced. Then, the hydrogen behaviors with the GASFLOW-MPI including the light gas release, stratification and dissolution are analyzed and validated with the experiment data. In addition, the velocity profiles, light gas concentrations, dimensionless numbers and temperature distributions are evaluated for the characteristics of the hydrogen behaviors. The results indicate that the calculation results agree well with the experiment data. Foremostly, the relative errors between the calculation results and experiment data during the phase of the dissolution of the light gas cloud are within 11.9%. Meanwhile, the relative errors of the time for the complete dissolution during the phase of the dissolution of the light gas cloud are within 5.0%. For the light gas release and stratification phase, the jet flow dominates as the Froude (Fr) number exceeds 10 during the time t = 600 s–800 s. Additionally, the time averaged centerline velocity and light gas concentration after the potential core region decay with a slop of 1/z which coincide with the theoretical jet limit. Lastly, the light gas concentrations and temperature distributions in all three phases are captured clearly with the GAFLOW-MPI. It demonstrates that the GASFLOW-MPI can accurately described the details of the related hydrogen behaviors in the accident and management process in the confined enclosure like the NPP. This paper can provide guidance for the numerical computation of the hydrogen safety issues in the confined space.

Two structural isomers of highly conjugated (bisthiophene)benzene carbazoles were designed and synthesized to study the effect of the substitution pattern on their liquid crystalline behavior, tran...

The INO80 chromatin remodeler is involved in many chromatin-dependent cellular functions. However, its role in pluripotency and cell fate transition is not fully defined. We examined the impact of Ino80 deletion in the naïve and primed pluripotent stem cells. We found that Ino80 deletion had minimal effect on self-renewal and gene expression in the naïve state, but led to cellular differentiation and de-repression of developmental genes in the transition toward and maintenance of the primed state. In the naïve state, INO80 pre-marked gene promoters that would adopt bivalent histone modifications by H3K4me3 and H3K27me3 upon transition into the primed state. In the primed state, in contrast to its known role in H2A.Z exchange, INO80 promoted H2A.Z occupancy at these bivalent promoters and facilitated H3K27me3 installation and maintenance as well as downstream gene repression. Together, our results identified an unexpected function of INO80 in H2A.Z deposition and gene regulation. We showed that INO80-dependent H2A.Z occupancy is a critical licensing step for the bivalent domains, and thereby uncovered an epigenetic mechanism by which chromatin remodeling, histone variant deposition and histone modification coordinately control cell fate.